This invention relates to an osteogenic osteoimplant made up of, at least in part, elongate bone-derived elements intended for use in the repair, replacement and/or augmentation of various portions of animal or human skeletal systems. More particularly, this invention relates to an implant made up of a mass of elongate bone-derived elements optionally in combination with bone powder. The elongate bone-derived elements and/or bone powder may be nondemineralized bone, partially or fully demineralized bone or any combination of the foregoing. An implant of the invention herein is especially suitable for use in periodontal applications, e.g., guided bone regeneration; plastic and reconstructive surgery, e.g., where the contour of the bone must be modified; and filling of cranial defects; though other skeletal applications are also envisioned.
The use of pulverized exogenous bone growth material, e.g., derived from demineralized allogenic or xenogenic bone, in the surgical repair or reconstruction of defective or diseased bone is known. See, in this regard, the disclosures of U.S. Pat. Nos. 4,394,370, 4,440,750, 4,472,840, 4,485,097, 4,678,470, and 4,743,259; Bolander et al., xe2x80x9cThe Use of Demineralized Bone Matrix in the Repair of Segmental Defectsxe2x80x9d, The Journal of Bone and Joint Surgery, Vol. 68-A, No. 8, pp. 1264-1273; Glowacki et al, xe2x80x9cDemineralized Bone Implantsxe2x80x9d, Symposium on Horizons in Plastic Surgery, Vol. 12, No. 2; pp. 233-241 (1985); Gepstein et al., xe2x80x9cBridging Large Defects in Bone by Demineralized Bone Matrix in the Form of a Powderxe2x80x9d, The Journal of Bone and Joint Surgery, Vol. 69-A, No. 7, pp. 984-991 (1987); Mellonig, xe2x80x9cDecalcified Freeze-Dried Bone Allograft as an Implant Material In Human Periodontal Defectsxe2x80x9d, The International Journal of periodontics and Restorative Dentistry, pp. 41-45 (June, 1984); Kaban et al., xe2x80x9cTreatment of Jaw Defects with Demineralized Bone Implantsxe2x80x9d, Journal of Oral and Maxillofacial Surgery, pp.623-626 (Jun. 6, 1989); and, Todescan et al., xe2x80x9cA Small Animal Model for Investigating Endosseous Dental Implants: Effect of Graft Materials on Healing of Endosseous, Porous-Surfaced Implants Placed in a Fresh Extraction Socketxe2x80x9d, The International Journal of Oral and Maxillofacial Implants Vol. 2, No. 4, pp. 217-223 (1987).
More recently, processed bone has been developed into new shapes for use in new surgical applications, or as new materials for implants that were historically made of non-biologically derived materials.
U.S. Pat. No. 4,678,470 describes a non-layered osteoimplanting material produced from bone by a process which includes tanning with glutaraldehyde. The bone may be pulverized, used as a large block or machined into a precise shape. The tanning stabilizes the material and also renders it non-antigenic but negatively impacts the osteoinductivity of the product. The bone material may also be demineralized.
U.S. Pat. No. 5,464,439 describes a continuous sheet of completely or partially demineralized natural bone having sufficient flexibility to conform to the implant site.
U.S. Pat. No. 5,556,430 describes the use of a continuous sheet of demineralized bone or partially demineralized bone, however, the sheet must be sufficiently flexible, therefore sacrificing strength, in order to conform to the skeletal site to which it is applied.
U.S. Pat. No. 5,507,813 describes a surgically implantable sheet formed from elongate bone-derived elements, optionally demineralized, containing biocompatible ingredients, adhesives, filler, plasticizers, etc.
U.S. Pat. No. 4,932,973 describes an artificial organic bone matrix with holes or perforations extending into the organic bone material. These holes or perforations are indicated to be centers of cartilage and bone induction following implantation of the bone matrix.
U.S. Pat. No. 4,394,370 describes a one-piece sponge-like osteoimplant material fabricated from filly demineralized bone powder or micro particulate bone, and reconstituted collagen. The sponge-like graft is optionally cross-linked with glutaraldehyde.
Another one-piece porous implant is described in U.S. Pat. No. 5,683,459. The implant is made up of a biodegradable polymeric macrostructure, which is structured as an interconnecting open cell meshwork, and a biodegradable polymeric microstructure composed of chemotactic ground substances such as hyaluronic acid.
U.S. Pat. No. 5,899,939 describes an osteoimplant fabricated from a number of layers possessing compression strength characteristics approximating those of natural bone.
However, the prior art demineralized bone products have proven to be unsatisfactory for applications requiring a thin osteogenic material capable of displaying a variety of properties. In one embodiment of the invention herein, the material is thin and conforming, i.e., able to be shaped closely to the exterior of bony surfaces, thereby minimizing stress on the overlying soft tissues. In a different embodiment of the invention herein, the material is form holding, i.e., able to maintain its three-dimensional architecture even after rehydration and deformation prior to or during implantation. Moreover, prior art products have been limited as to the size and shape of the finished product by the size and type of starting material used to form the product. In every embodiment of the invention herein the size of the implant is limited only by the total amount of starting material available and not by the size and type of starting material. Thus, a thin osteogenic material capable of displaying a variety of properties would be highly desirable.
Therefore, it is an object of the invention to provide an osteogenic osteoimplant having a void volume of not greater than about 32% prepared by providing, at least in part, elongate bone-derived elements in a coherent mass and mechanically shaping the mass.
It is a further object of the invention to provide an osteogenic osteoimplant made up of, at least in part, elongate bone-derived elements which is capable of being three-dimensionally shaped prior to implantation to provide for, say, the specific architecture of an implant site.
It is a further object of the invention to provide an osteogenic osteoimplant consisting of a laminate formed at least in part from the osteoimplant of the invention herein.
It is a further object of the invention to provide an osteogenic osteoimplant made up of fully demineralized bone elements that is membrane like yet capable of holding its shape and volume despite pressure from overlying gingival tissue, i.e., shape retaining.
It is yet a further object of the invention to provide a highly flexible, highly conformable, osteogenic osteoimplant by adding a bio-compatible fluid carrier to the fully demineralized bone-derived elements, the carrier remaining in the implant even after dehydration.
It is yet a further object of the invention to provide an osteogenic osteoimplant wherein one surface is less penetrable by cells.
It is yet a further object of the invention to provide an osteogenic osteoimplant which can be tailored to have varied permeability and handling characteristics.
It is yet a further object of the invention to provide an osteogenic osteoimplant in which at least one surface can be treated to produce a visible pattern.
It is yet a further object of the invention to provide an osteogenic osteoimplant whose size is limited only by the amount of starting materials available.
In keeping with these and related objects of this invention, there is provided an osteogenic osteoimplant in the form of a flexible sheet having not greater than about 37% void volume comprising a coherent mass of bone-derived particles. This is in contrast to the shaped materials prepared in accordance with U.S. Pat. No. 5,507,813 that have a void volume of at least about 37% and the load-bearing materials prepared in accordance with U.S. patent application Ser. No. 09/256,447 filed Feb. 23, 1997 which have a wet compressive strength of at least about 3 MPa.
Although not wishing to be bound by theory, it is believed that the relatively small void volume of the osteoimplant of this invention allows for the improved properties as compared to like materials that have a void volume of greater than about 32%.
The osteogenic osteoimplant of this invention is much thinner than prior art osteoimplants, i.e., thickness ranging from about 50 microns to about 2000 microns being entirely suitable. In one embodiment, the osteogenic osteoimplant of the invention herein can be contoured to a specific three-dimensional architecture that is retained even after rehydration. This form holding embodiment of the invention is able to be incorporated as a graft into the implant site and retains its architecture even after deformation prior to or during implantation while providing an implant that can interact biologically with the host tissue.
In a different embodiment of the invention, the fully demineralized bone-derived particles, i.e., elongate bone-derived elements and/or bone powder, are combined with a suitable biocompatible fluid carrier that remains in the implant, even after dehydration, to provide a conformable material. This embodiment of the invention does not have a shape memory in contrast to implants made from thin sections of monolithic demineralized bone as disclosed in U.S. Pat. No. 4,932,973 and is therefore able to be shaped closely to the exterior of a bony surface thereby conforming to a bone-grafted surface. Because this embodiment of the osteoimplant is thin and conformable, the osteoimplant minimizes stress on the overlying soft tissues when they are closed over the bone-grafted site. In addition, the thin membrane-like configuration of this embodiment of the invention allows for its placement between other osteoimplant materials, e.g., allograft and/or autograft, and gingival tissues in ridge augmentation and/or periodontal repair procedures. In a preferred embodiment of the invention herein, the fully demineralized bone-derived implant of this invention, acting as an impermeable membrane, serves primarily as a barrier membrane imparting osteogenic osteoimplant like properties while preventing ingrowth of soft tissues. This is especially important in the instance where the tissue cannot be closed completely or tightly over the bone-grafted site, e.g., ridge augmentation. This is in contrast to prior art products whose flexibility is inadequate for use in facilitating closure during such procedures.
In each of the different embodiments of the invention, the osteogenic osteoimplant prepared according to the method of this invention is not limited as to its final size by the anatomic constraints of the bone-derived elements from which it is made, but rather, it is capable of being made to any size so long as an appropriate amount of starting material is available. In addition, each of the different embodiments is flexible when in the hydrated state. The term xe2x80x9cflexiblexe2x80x9d as utilized herein refers to the ability of the unsupported implant to be deformed by the application of a force or combination of forces, e.g., compressive, flexural, etc.
The term xe2x80x9cbonexe2x80x9d as used herein refers to bone that is cortical, cancellous or cortico-cancellous of autogenous, allogenic, xenogenic or transgenic origin.
The term xe2x80x9cdemineralizedxe2x80x9d as used herein refers to bone containing less than its original mineral content and is intended to encompass such expressions as xe2x80x9csubstantially demineralizedxe2x80x9d, xe2x80x9cpartially demineralizedxe2x80x9d and xe2x80x9cfully demineralizedxe2x80x9d.
As utilized herein, the expression xe2x80x9csuperficially demineralizedxe2x80x9d refers to bone-derived elements possessing at least about 90 weight percent of their original inorganic mineral content, the expression xe2x80x9cpartially demineralizedxe2x80x9d refers to bone-derived elements possessing from about 8 to about 90 weight percent of their original inorganic mineral content and the expression xe2x80x9cfully demineralizedxe2x80x9d refers to bone containing less than 8% of its original mineral context.
The term xe2x80x9costeoimplantxe2x80x9d as used herein refers to any bone-derived implant prepared in accordance with the embodiments of this invention and therefore is intended to include expressions such as bone membrane, bone graft, etc.
The term xe2x80x9costeogenicxe2x80x9d as applied to the osteoimplant of this invention shall be understood as referring to the ability of the osteoimplant to enhance or accelerate the ingrowth of new bone tissue by one or more mechanisms such as osteoinduction and/or osteoconduction.
The term xe2x80x9costeoinductivexe2x80x9d as used herein shall be understood to refer to the ability of a substance to recruit and transform cells from the host which have the potential for repairing bone tissue.
The term xe2x80x9costeoconductivexe2x80x9d as used herein shall be understood to refer to the ability of a substance to provide biologically inert surfaces which are receptive to the growth of new host bone.
The term xe2x80x9ccoherentxe2x80x9d as applied to the mass of bone-derived elements refers to the ability of the bone-derived elements to adhere to each other either mechanically, e.g., by entanglement, or bending; or, by the use of a biocompatible matrix regardless of whether the mass of bone-derived elements is in the dry or wetted, i.e., hydrated, state.
The expression xe2x80x9cmechanically shapingxe2x80x9d or expressions of similar import as used herein shall be understood as referring to the application of external forces, e.g., compressive, lateral, etc., to the coherent mass of bone-derived elements through any suitable means, e.g., pressing, rolling, etc.
The expression xe2x80x9cvoid volumexe2x80x9d as used herein shall be understood to refer to the amount of non-solid space contained within the implant of this invention and is determined by averaging the area of white space in each field of stained sections of the implant. Such space will be considered to be void volume even if it contains a substance that is liquid at ambient temperature, e.g., 0.5xc2x0 to 50xc2x0 C.
The expression xe2x80x9cform holdingxe2x80x9d as applied to this invention refers to the ability of the implant to be deformed prior to or during implantation and then characteristically returning to its original architecture after implantation.
The term xe2x80x9cshape retainingxe2x80x9d as utilized herein refers to the ability of the implant to maintain a predetermined shape even after its rehydration and/or implantation.
The expression xe2x80x9cnon-load-bearingxe2x80x9d as utilized herein refers to the unsuitability of the invention herein to be utilized in load-bearing applications, i.e., applications where the osteoimplant would be expected to withstand the application of compressive force along its major dimensions. Rather, the invention herein is envisioned as being suitable for those applications where the load applied to the implant, if any, would be largely flexural or tensile in nature. Of course, some compressive force will be applied to the osteoimplant due to the force(s) exerted by the tissue(s) overlying the osteoimplant, however, such force(s) would be applied along the minor dimension and would not be of such magnitude as to be considered as clinically xe2x80x9cload-bearingxe2x80x9d.
The expression xe2x80x9cguided bone regenerationxe2x80x9d (GBR) or xe2x80x9cguided tissue regenerationxe2x80x9d (GTR) as applied to this invention refers to the ability of the implant to induce sufficient bone growth before competitive, faster-growing soft tissue and epithelial cells fill the bone repair site.
The term xe2x80x9coccludingxe2x80x9d as utilized herein shall be understood to refer to any operation or process which reduces the porosity of a region of the ostegenic osteoimplant thus rendering such surface area substantially impermeable to the ingrowth of soft tissue, i.e., undesired cells and soft tissues that are competitive to bone formation.
The term xe2x80x9cintegralxe2x80x9d as utilized herein is intended to differentiate the ostegenic osteoimplant of this invention from osteoimplants which are combined with a separate barrier membrane material. In the instant invention, the osteoimplant and zone of impermeability are integral with one another, i.e., they are indivisibly interconnected so as to form a single, unified whole.
Use of the expression xe2x80x9cbone-derived elementsxe2x80x9d or expressions of like import, shall be understood as referring to pieces of bone in any variety of sizes, thicknesses and configurations including elongate particles, particles, fibers, strips, powders etc., which can be obtained by milling, shaving, cutting or machining whole bone with the proviso that such elements are not envisioned as containing layers as set forth in U.S. Pat. No. 5,899,939.